J Pharm Sci. 2019 Jun;108(6):2180-2190. doi: 10.1016/j.xphs.2019.01.024. Epub 2019 Feb 2.

Whole-Body Physiologically Based Pharmacokinetic Modeling of Trastuzumab  and Prediction of Human Pharmacokinetics.

Bae DJ, Kim SY, Bae SM, Hwang AK, Pak KC, Yoon S, Lim HS.

Abstract

In the present study, we evaluated the pharmacokinetics (PK) of trastuzumab and sought to predict human PK based on animal studies, through the use of optical imaging and a whole-body physiologically based pharmacokinetic (WB-PBPK) modeling approach. The PK study was conducted in 24 mice, where serial blood samples were withdrawn and major organs were isolated after the last blood withdrawal. The drug concentrations in blood and major organs were measured via optical imaging. The WB-PBPK model was constructed using known physiological values including the volumes of major organs and blood/lymphatic flow. The NONMEM software (version 7.3) was used to determine tissue partition coefficients. Using the WB-PBPK model, a clinical trial simulation was performed with reference to human physiological values acquired from the literature. The simulated human PK was then compared with the actual PK observed in the previous study in which healthy male subjects received 6 mg/kg trastuzumab (Herceptin®) via intravenous route. The ratio of the simulated versus observed area under the concentration-time curve was 1.02 and that of maximal concentration was 0.72. The current study describes the potential synergistic applications of WB-PBPK and optical imaging in human PK prediction based on preclinical data obtained in early-stage drug development.

KEYWORDS:

NONMEM; human prediction; monoclonal antibody; optical imaging; whole-body physiologically based  pharmacokinetics

PMID:

30716331

DOI:

10.1016/j.xphs.2019.01.024